First-degree Relatives Of Diabetic Patients Research Articles

Novel anthropometric indices for predicting type 2 diabetes mellitus

BackgroundThis study aimed to compare anthropometric indices to predict type 2 diabetes mellitus (T2DM) among first-degree relatives of diabetic patients in the Iranian community.MethodsIn this study, information on 3483 first-degree relatives (FDRs) of diabetic patients was extracted from the database of the Endocrinology and Metabolism Research Center of Isfahan University of Medical Sciences. Overall, 2082 FDRs were included in the analyses. A logistic regression model was used to evaluate the association between anthropometric indices and the odds of having diabetes. Furthermore, a receiver operating characteristic (ROC) curve was applied to estimate the optimal cutoff point based on the sensitivity and specificity of each index. In addition, the indices were compared based on the area under the curve (AUC).ResultsThe overall prevalence of diabetes was 15.3%. The optimal cutoff points for anthropometric measures among men were 25.09 for body mass index (BMI) (AUC = 0.573), 0.52 for waist-to-height ratio (WHtR) (AUC = 0.648), 0.91 for waist-to-hip ratio (WHR) (AUC = 0.654), 0.08 for a body shape index (ABSI) (AUC = 0.599), 3.92 for body roundness index (BRI) (AUC = 0.648), 27.27 for body adiposity index (BAI) (AUC = 0.590), and 8 for visceral adiposity index (VAI) (AUC = 0.596). The optimal cutoff points for anthropometric indices were 28.75 for BMI (AUC = 0.610), 0.55 for the WHtR (AUC = 0.685), 0.80 for the WHR (AUC = 0.687), 0.07 for the ABSI (AUC = 0.669), 4.34 for the BRI (AUC = 0.685), 39.95 for the BAI (AUC = 0.583), and 6.15 for the VAI (AUC = 0.658). The WHR, WHTR, and BRI were revealed to have fair AUC values and were relatively greater than the other indices for both men and women. Furthermore, in women, the ABSI and VAI also had fair AUCs. However, BMI and the BAI had the lowest AUC values among the indices in both sexes.ConclusionThe WHtR, BRI, VAI, and WHR outperformed other anthropometric indices in predicting T2DM in first-degree relatives (FDRs) of diabetic patients. However, further investigations in different populations may need to be implemented to justify their widespread adoption in clinical practice.

Insulin Resistance in Type II Diabetes Mellitus Patients and Their First Degree Relatives- An Observational Study

Type II diabetes (T2DM) is caused by environmental, genetic, metabolic, and unknown variables. In diabetics, insulin resistance is the most of prolonged hyperglycemia. T2DM is induced by insulin resistance and cell dysfunction. The interaction of genetics and environment further complicates T2DM development. Insulin resistance and beta cell dysfunction are two of the most common Type 2 Diabetes Mellitus symptoms. A vicious triangle of cell failure (80% cell function) and insulin resistance in the muscles and liver causes major physiological issues. A group of diabetes patients (Group I), non-diabetic first-degree relatives of diabetic patients (Group II), and a non-diabetic healthy control group (Group III) were studied. The diabetes patients had the greatest systolic and diastolic blood pressures, followed by first degree relatives and healthy controls. We found that people with diabetes had higher fasting (FBS) and postprandial sugar, glycated haemoglobin (HbA1c) than diabetic offsprings and control group. Moreover, fasting insulin levels are higher in first degree relatives than in diabetes patients in the control group. The HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) levels of diabetics and their progeny do not differ much. The HOMA-IR measures insulin resistance severity. Common reference levels for HOMA-IR insulin resistance range from 0.7 - 2. Insulin resistance in diabetics and their first-degree relatives is evident from the results.

Acute ingestion of a high-fructose drink impairs vascular autonomic modulation and reflex control of blood pressure in first-degree relatives of diabetic patients

First-degree relatives of diabetes patients, despite being euglycemic, presented impaired BRS and exacerbation of sympathetic modulation after ingestion of a high fructose drink when challenged to orthostatic stress. This finding alerts the importance of early autonomic dysfunction even in clinically healthy people, especially in face of a stressful situation.

Prevalence and predictors of prediabetes and its coexistence with high blood pressure in first-degree relatives of patients with type 2 diabetes: A 9-year cohort study.

Background:Prediabetes is strongly associated with high blood pressure; however, a little is known about prediabetes and high blood pressure comorbidity in the high-risk individuals. This is the first study in the world to assess the long-term effects of risk factors associated with high blood pressure and prediabetes comorbidity in the first-degree relatives (FDRs) of type 2 diabetes mellitus (T2DM) patients.Materials and Methods:The longitudinal data obtained from 1388 nondiabetic FDRs of T2DM patients with at least two visits between 2003 and 2011. We used univariate and bivariate mixed-effects logistic regressions with a Bayesian approach to identify longitudinal predictors of high blood pressure and prediabetes separately and simultaneously.Results:The baseline prevalence of high blood pressure, prediabetes, and the coexistence of both was 27.4%, 19.1%, and 29.8%, respectively. The risks of high blood pressure and prediabetes were increased by one-unit raise in the age (odds ratio [OR] of high blood pressure: 1.419 (95% credible intervals [CI], 1.077–1.877), prediabetes: 1.055 (95% CI: 1.040–1.068)) and one-unit raise in remnant-cholesterol (OR of high blood pressure: 1.093 (95%CI, 1.067–1.121), and prediabetes: 1.086 (95% CI, 1.043–1.119)). Obese participants were more likely to have high blood pressure (OR: 2.443 [95% CI, 1.978–3.031]) and prediabetes (OR: 1.399 [95% CI, 1.129–1.730]) than other participants.Conclusion:We have introduced remnant-cholesterol, along with obesity and age, as a significant predictor of prediabetes, high blood pressure, and the coexistence of both in the FDRs of diabetic patients. Obesity index and remnant-cholesterol showed the stronger effects on high blood pressure and prediabetes comorbidity than on each condition separately.

Predicting Diabetes in Relatives of Diabetic Patients Using Insulinoma Antigen-2 Antibody-A Biomarker for Type 1 Diabetes in Jos, Nigeria

Background: Type 1 diabetes is a chronic autoimmune disease caused by the destruction of insulin-secreting islet cells of the pancreas by several islet cell-specific autoantibodies that can be detected many months or years before the onset of diabetes. The presence of these antibodies can be attributed largely to environmental agents and also genetic factors. Knowing the frequency of these autoantibodies in a population is an important step for a better understanding, diagnosis and management of Type 1 diabetes. The aim of the research was to screen and identify those at greatest risk of diabetes (relatives of diabetic patients) early in life, as a precautionary step with the hope to deliver care in order to avoid the disease and its complications later in life. Method: The study was conducted on eighty-eight apparently healthy young and adolescent first-degree relatives of diabetic patients in Jos metropolis. Blood samples were collected, centrifuged and serum was aseptically separated within two hours. A commercial ELISA test kit - Medizym® anti-IA2 was used to determine the presence of anti-IA-2 autoantibodies in serum obtained from participants enrolled in the study. Results: The results obtained showed twelve participants of both sexes (13.64%) having positive titers of the IA-2 antibodies which were statistically significant. Conclusion: From the results, we conclude that with significant titers of the IA-2 antibodies among young adolescents, there is the likelihood of them developing diabetes later in life depending on the period of exposure to the factors responsible for triggering the autoimmune process. The results are hereby discussed and recommendations made.

Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage

BackgroundFirst-degree relatives of type-2 diabetes patients (FDR) present insulin resistance. We investigated whether FDR and dysglycaemic subjects demonstrate abnormal endothelial glycocalyx and LV deformation during postprandial hyperglycemia. MethodsWe studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic). At 0 and 120min of OGTT we measured: a) LV longitudinal strain (LS) of subendocardial, mid-myocardial and subepicardial layers, global LS (GLS), peak twisting (pTw), untwisting velocity (pUtwVel), by speckle tracking echocardiography b) perfused boundary region (PBR) of the sublingual arterial microvessels; high PBR values represent reduced glycocalyx thickness. Insulin resistance was evaluated using insulin sensitivity index (ISI). ResultsISI was related with baseline PBR, GLS and pTw in all subjects (p<0.05). Compared to normoglycaemics, FDR and dysglycaemics had higher PBR, lower ISI, GLS (−18.4±2.6 and −16.8±2.0 vs. −19.2±2.4%), subendocardial LS (−19.0±4.2 and −17.9±3.0 vs. −20.1±3.4%), pTw (14.4±4.4 and 15.6±6.4 vs. 16.9±6.5deg) and pUtwVel (p<0.05 for all comparisons). A GLS<−18% identified FDR with LV dysfunction (p=0.016).Post-OGTT, GLS and the subendocardial LS decreased while pTw and pUtwVel increased in FDR and dysglycaemics (p<0.05) indicating prevalence of the motion of the subepicardial over a dysfunctioning subendocardial myocardial helix. Increased PBR was related with impaired deformation markers at baseline and 120min of OGTT (p<0.05). ConclusionFirst-degree relatives and dysglycaemics have reduced glycocalyx thickness related with impaired LV longitudinal, twisting-untwisting function. Postprandial hyperglycemia when combined with insulin resistance causes LV longitudinal dysfunction leading to increased LV twisting.

Heart rate variability in nondiabetic dyslipidemic young Saudi adult offspring of type 2 diabetic patients

Background: Autonomic imbalance has been described in first-degree relatives of diabetic patients, and dyslipidemia has been reported to induce sympathovagal imbalance (SVI). Aims and Objective: To assess the contribution of dyslipidemia to SVI in adults with positive family history of type 2 diabetes mellitus (T2DM). Materials and Methods: This is a cross-sectional study involving 150 male Saudi adults aged 19–30 years, recruited from students of College of Applied Medical Sciences in Taif University, Taif, Saudi Arabia. Lipid profile, atherogenic index (AI), body mass index (BMI), waist circumference (WC), basal heart rate (BHR), blood pressure (BP), spectral indices of heart rate variability (HRV), and homeostatic model of insulin resistance (HOMA-IR) were measured and analyzed in study groups (control subjects with no family history of T2DM, n = 50; positive family history of T2DM, nondyslipidemic subjects, n = 50 and dyslipidemic subjects n = 50). Result: In the dyslipidemic group, lipid profile, LF-HF (ratio of low-frequency to high-frequency power of HRV, a precise indicator of SVI) was significantly increased (P˂ 0.05) when compared with non dyslipidemic and the control groups. Increased SVI was owing to simultaneous sympathetic motivation and vagal inhibition. LF-HF ratio was positively correlated with the WC, SBP, DBP, BHR, total cholesterol (TC), low-density lipoprotein (LDL) and AI. Significant contribution of WC, DBP, BHR, TC, and AI to the LF-HF ratio in the dyslipidemic group was observed by multiple regression analysis. Conclusion: SVI in dyslipidemic subjects with family history of T2DM occurs owing to sympathetic activation and vagal depression. Dyslipidemia contributes to the SVI in these subjects.

Insulin resistance and acute glucose changes determine arterial elastic properties and coronary flow reserve in dysglycaemic and first-degree relatives of diabetic patients.

Insulin resistance is linked to endothelial dysfunction. We investigated whether first-degree relatives of type-2 diabetes patients (FDR) present differences in vascular function at baseline and during postprandial hyperglycemia compared to dysglycaemic or normoglycaemic subjects. We studied 40 FDR with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic) with similar clinical characteristics. Glucose, insulin, pulse wave velocity (PWV), central systolic blood pressure (cSBP) and augmentation index (AI) were measured at 0, 30, 60, 90 and 120min during OGTT. Coronary flow reserve (CFR) was assessed using Doppler echocardiography at 0 and 120min after OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). FDR and dysglycaemics had higher fasting insulin, reduced ISI, Matsuda index as well as reduced CFR (2.54±0.5 vs. 2.45±0.3 vs. 2.74±0.5), increased PWV, (8.9±1.1 vs. 10.3±2.4vs. 8.0±1.5m/sec), AI (23.8±13.6 vs. 26.5±14.4vs.17.7±14%) and cSBP than normoglycaemics (p<0.05 for all comparisons). During OGTT, AI was similarly reduced in both normoglycaemic and FDR (p<0.05) at peak insulin levels (60min) though FDR had 2-fold higher insulin than normoglycaemics. AI was increased in dysglycaemics after peak glucose levels, at 120min (p<0.05). CFR was reduced by 10% and 15% at 120min in FDR and dysglycaemic respectively, while remained unchanged in normoglycaemics (p<0.05). The percent reduction of CFR was related with the percent increase of glucose levels, ISI and Matsuda index(p<0.05). First-degree relatives and dysglycaemic patients have impaired arterial and coronary microcirculatory function. Insulin resistance determines acute vascular responses during postprandial hyperglycemia. CLINICALTRIALS. NCT02244736.

Prognostic markers for the development of type 1 diabetes in first-degree relatives of diabetic patients.

The aim of this study was to evaluate beta-cell function and insulin resistance in relation to the occurrence of anti-islet antibodies in first degree relatives of patients with type 1 diabetes (T1D). The group studied consisted of 90 relatives and 60 healthy individuals without a family history of diabetes. An intravenous glucose tolerance test (IVGTT) was performed in all participants and the first phase insulin response index (FPIR) was calculated. Serum concentrations of GADA, IAA and IA-2A were measured by RIA. HOMA-IR and HOMA%B indices were calculated using a computer calculator from website. At least one positive antibody was found in 28 relatives (31.1%) but in none of the controls. The most frequently detected antibodies were IAA (22.2%). The relatives of diabetic patients had significantly higher fasting insulin level (p), significantly lower FPIR index(p), as well as higher HOMA-IR (p) and lower HOMA%B (p) compared to the controls. A positive correlation between IAA concentration and HOMA-IR (r = 0.287, p < 0.005) and a negative correlation between IAA level and HOMA%B (r = -0.226, p < 0.05) were also shown. Our results confirmed that more than 30% of the first-degree relatives of diabetic patients have positive markers of autoimmune beta-cell destruction. The study showed also that these individuals, in spite of normal glucose tolerance, have markedly decreased beta-cell secretory reserve and decreased sensitivity to insulin action, strongly suggesting an increased risk for developing diabetes later in life.

Association of hypertension status and cardiovascular risks with sympathovagal imbalance in first degree relatives of type 2 diabetics.

As reports show cardiovascular (CV) risks in first-degree relatives (FDR) of type2 diabetics, and autonomic imbalance predisposing to CV risks, in the present study we have assessed the contribution of sympathovagal imbalance (SVI) to CV risks in these subjects. Body mass index (BMI), waist-to-hip ratio (WHR), basal heart rate (BHR), blood pressure (BP), rate pressure product (RPP), and spectral indices of heart rate variability (HRV) were reordered and analyzed in FDR of type2 diabetics (study group, n=293) and in subjects with no family history of diabetes (control group, n=405). The ratio of low-frequency (LF) to high-frequency (HF) power of HRV (LF-HF), a sensitive marker of SVI, was significantly increased (P<0.001) in the study group compared with the control group. The SVI in the study group was due to concomitant sympathetic activation (increased LF) and vagal inhibition (decreased HF). In the study group, the LF-HF ratio was significantly correlated with BMI, WHR, BHR, BP and RPP. Multiple regression analysis showed an independent contribution of LF-HF to hypertension status (P=0.000), and bivariate logistic regression showed significant prediction (odds ratio 2.16, confidence interval 1.130-5.115) of LF-HF to increased RPP, the marker of CV risk, in the study group. Sympathovagal imbalance in the form of increased sympathetic and decreased parasympathetic activity is present in FDR of type2 diabetics. Increased resting heart rate, elevated hypertension status, decreased HRV and increased RPP in these subjects make them vulnerable to CV risks. SVI in these subjects contributes to CV risks independent of the degree of adiposity.

Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity

Reduced early insulin response has been shown to predict type 1 diabetes (T1D) in first-degree relatives of diabetic patients, while its role, as well as that of insulin resistance, has remained poorly defined in young children representing the general population. The predictive values of these markers and their relation to other risk factors of T1D were assessed in children with advanced β-cell autoimmunity, i.e. persistent positivity for two or more autoantibodies. Intravenous glucose tolerance tests (IVGTTs) were carried out in 218 children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Baseline, metabolic and growth data were compared between children progressing to diabetes and those remaining unaffected. Hazard ratios for the disease predictors and the progression rate of T1D were assessed. Children developing T1D were younger at seroconversion, progressed more rapidly to advanced β-cell autoimmunity and had lower first-phase insulin response (FPIR) and homeostasis model assessment index for insulin resistance (HOMA-IR) than those remaining non-diabetic. The levels of HOMA-IR/FPIR, islet cell antibodies, insulin autoantibodies (IAA) and islet antigen 2 antibodies (IA-2A) were higher in progressors. BMI SDS, FPIR, age at IVGTT and levels of IAA and IA-2A were predictive markers for T1D. Young age, higher BMI SDS, reduced FPIR and higher levels of IAA and IA-2A predicted T1D in young children with HLA-DQB1-conferred disease susceptibility and advanced β-cell autoimmunity. Disease risk estimates were successfully stratified by the assessment of metabolic status and BMI. The role of insulin resistance as an accelerator of the disease process was minor.

MODY

Studies conducted at the University of Michigan for 60 years and at the University of Chicago for approximately 25 years form the basis of this review. As no field of study can develop or progress in isolation, we have included selected investigations performed in other centers. In the academic year 1949–1950, one of us (S.S.F.), while a first-year Fellow in Endocrinology and Metabolism at the University of Michigan (Jerome W. Conn, Division Chief), initiated a prospective, long-term study on the diagnosis, natural history, and clinical genetics of diabetes. Starting with known diabetic patients from the Diabetes Clinic, I recruited their apparently healthy and asymptomatic first-degree relatives (parents, brothers, sisters, and children) for routine oral glucose tolerance tests (OGTTs). As control subjects, I recruited young individuals, many of them students, physicians, nurses, dietitians, and their spouses, who did not have a family history of diabetes or of large newborn babies. The initial objectives were 1 ) to define the normal range for the OGTT, 2 ) to attempt to unmask the potential diabetic subjects who manifest normal glucose tolerance by the standard OGTT and determine whether the diabetogenic activity of cortisone could be used to uncover a subclinical defect in the metabolism of glucose, and 3 ) to carry out periodic follow-up over many years of the apparently healthy first-degree relatives of diabetic patients. In our first publication in 1954 (1), 19% of 152 relatives of known diabetic patients were found to have diabetes by OGTT and, moreover, some were as young as 10 years of age. The same prevalence of 19% was found when testing a larger sample of 438 relatives of known diabetic patients (2). In 1960, we reported that mild, asymptomatic diabetes occurs in nonobese children, adolescents, and young adults. Their diabetic glucose tolerance and fasting hyperglycemia improved or normalized …

Selenium Levels in First-Degree Relatives of Diabetic Patients

The present study was conducted to evaluate the serum selenium levels in first-degree relatives of diabetic patients (FDR) according to controls. Insulin resistance, serum lipid levels, inflammation markers, and blood pressure were also studied in these patients. Serum levels of selenium in FDR were significantly lower than control group (74.65 +/- 5.9 vs 88.7 +/- 8.7 microg/dl, p < 0.0001). HsCRP, HOMA-IR, insulin, homocysteine levels were significantly higher in FDR according to the control group (1.32 +/- 0.9 vs 0.63 +/- 0.4 mg/dL, p < 0.0001; 2.07 +/- 0.84 vs 1.51 +/- 0.69, p < 0.0001; 9.26 +/- 3.8 vs 6.8 +/- 2.98 microU/MI, p < 0.0001; 15.7 +/- 7.4 vs 11.5 +/- 5.1 micromol/L, p < 0.0001, respectively). There was significant correlation between selenium levels and hsCRP (r = - 0.450, p < 0.0001). There was also weak significant correlation also between HOMA-IR and selenium levels (r = -0.227, p = 0.003). There was a correlation between systolic blood pressure and BMI (r = 0.365, p < 0.0001). But there was no correlation between selenium levels and blood pressure or other parameters. HsCRP, HOMA-IR, homocysteine levels in individuals with selenium levels < 80 microg/L (n = 78) was significantly higher than hsCRP HOMA-IR, homocysteine levels in individuals with selenium levels >or= 80 (n = 91; 1.23 +/- 0.98 vs 0.81 +/- 0.76 mg/dL, p < 0.003; 1.99 +/- 0.88 vs 1.64 +/- 0.74, p < 0.005; 15.0 +/- 7.6 vs 12.9 +/- 5.7 micromol/L, p < 0.049, respectively). Selenium deficiency may contribute to cardiovascular disease risk in FDR.

Quality of Care for First-Degree Relatives of Type 2 Diabetes Patients Diagnosed with Diabetes at a Screening Program One Year After Diagnosis

Diabetes screening is an effective tool for diagnosing patients who are unaware of their diabetes and for providing them with optimal treatment. The quality of care and treatment of diabetic patients diagnosed at a screening program during one year in Isfahan, a centrally located Iranian city, was assessed. In a prospective study, 1640 first-degree relatives of diabetic patients (aged 35-55) were screened for diabetes mellitus at Isfahan Endocrine and Metabolism Research Center during 2003-2004. All patients diagnosed with diabetes during screening were selected and their height, weight, blood pressure, fasting plasma glucose, lipids and HbA1c were recorded at the time of diagnosis and one year later. The values at the time of screening were subsequently compared with those collected one year later. Eighty-three subjects (5.06%) were diagnosed with diabetes during screening. Of these patients, 78.3% were dyslipidemic and 45% were hypertensive. One year after diagnosis, 77.1% of patients were receiving treatment for hyperglycemia. However, only 49.2% of dyslipidemic and 45% of hypertensive patients were being treated for these conditions. Body mass index, fasting plasma glucose, lipids and HbA1c had improved one year after diagnosis, but no significant improvement was observed in blood pressure. The evaluation of the quality of care for newly diagnosed diabetic patients revealed that more attention should be paid to glycemic control and reducing cardiovascular risk factors, in particular hypertension.

Endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives of diabetic patients are independent of the metabolic syndrome

Background and aim The aim of the present study was to investigate endothelial function and arterial stiffness in normotensive normoglycemic first-degree relatives (offspring) of diabetic subjects and to explore the relationship with the metabolic syndrome and its components. Methods and results Forty-five healthy normotensive normoglycemic subjects (aged 18–42 years), 29 first-degree relatives of diabetic subjects (FDR) and 16 with no parental history of type 2 diabetes mellitus were studied. Endothelial function was measured as flow-mediated dilation of the brachial artery (FMD) and arterial stiffness as carotid-femoral pulse wave velocity (PWV). Insulin resistance was calculated by homeostasis model assessment (HOMA). Plasma levels of inflammation markers (hsCRP, TNF-α, IL-1β, CD40L, VCAM, and ICAM) were evaluated. Normotensive normoglycemic FDR presented a 33% lower flow-mediated dilation than the control group (9.8 ± 5.2 vs. 16.2 ± 7.6%, p < 0.01). FMD was reduced in FDR, with or without insulin resistance, whereas arterial stiffness was significantly increased only in FDR with insulin resistance. To investigate the role of FDR status independently of altered components of the metabolic syndrome, subjects with no altered components of the metabolic syndrome were compared according to their FDR status: FDR subjects with no altered components of the metabolic syndrome presented a blunted endothelial function (lower FMD: 11.2 ± 1.6 vs. 16.8 ± 2.0%, p < 0.05) and stiffer large arteries (higher PWV: 9.6 ± 0.3 vs. 8.8 ± 0.3 m/s, p < 0.05) than controls. Conclusion Normoglycemic first-degree relatives of diabetic subjects have blunted endothelial function and increased stiffness of the large arteries. These alterations are already present at a very young age, before any alteration in glycemic control or blood pressure values can be detected, and are independent of the presence of the metabolic syndrome and its altered components.

Clinique et diagnostic du diabète de l'enfant

Childhood diabetes mellitus is mostly insulin-dependent and caused by autoimmune destruction of the pancreatic islet β-cells (type 1 diabetes). The annual incidence is increasing in France, reaching now 10 new cases/100 000 children between 0 and 15 years of age. Approximately 75 % of diabetes are diagnosed on polyuria, polydipsia, polyphagia, and weight loss. Ketoacidosis occurs in 25 % of newly diagnosed diabetes. Diagnostic criteria for diabetes mellitus include symptoms of diabetes associated with a random plasma glucose > 200 mg/dl. Bêta-cell autoantibodies (ICA, anti-GAD, anti-insulin and anti-IA2) are present in at least 90 % of children with newly diagnosed diabetes. Ketoacidosis in subjects with established diabetes often results from a deliberate cessation of insulin treatment in adolescents. The manifestations are tachypnea and abdominal pain. The major life-threatening complications of ketoacidosis are hypokaliemia, pulmonary aspiration, and cerebral edema, with 1-2 % mortality. Hypoglycemia is defined by plasma glucose less than 60 mg/dl. The clinical manifestations correspond to the adrenergic response (minor hypoglycemia), followed by neuroglycopenia (severe hypoglycemia). Hypoglycemia unawareness occurs in most of the patients with type 1 diabetes after > 5 years of diabetes duration, increasing the risk of severe hypoglycemia. Diagnosis of diabetic microvascular complications is based on annual microalbuminuria measurement and fundus examination in diabetic adolescents with at least 5 years of diabetes duration. Diabetes prediction in first-degree relatives of diabetic patients relies on the detection of multiple diabetes-associated autoantibodies. Rare forms of childhood non-autoimmune diabetes include neonatal diabetes, MODY (maturity-onset diabetes of the young), Wolfram syndrome, mitochondrial diabetes and type 2 diabetes….

Neonatal Nutritional Interventions in the Prevention of Type 1 Diabetes

After completing this article, readers should be able to: 1. Outline the current concepts of the pathogenesis of type 1 diabetes (T1D) with regard to dietary triggers and genetic susceptibility. 2. Discuss the evidence, both epidemiologic and that derived from studies of animal models, that supports the association between infant feeding practices and T1D. 3. Describe the roles for intestinal immunity and permeability in supporting the hypothetical model of cow milk protein mediation of T1D autoimmunity. 4. Delineate the goals and rationale for prospective clinical trials evaluating neonatal nutrition and the development of T1D. 5. List the putative dietary modulators of T1D. Type 1 diabetes (T1D), a disease that has unacceptably high morbidity and mortality, is increasing in incidence, prompting the redoubling of efforts toward its prevention. Progress toward prevention and cure relies on elucidation of the disease’s pathogenesis, which, to date, has remained poorly defined. The defining features of T1D, insulin deficiency and hyperglycemia, result from an immune-mediated destruction of insulin-secreting beta cells in the pancreatic islets. The loss of beta cell mass is believed to be gradual for most individuals, accounting for the sometimes prolonged asymptomatic periods of autoimmunity preceding overt diabetes (Fig. 1). Indeed, the chronic autoimmune nature of the disease is well established, as is the genetic predisposition. Specific associations with molecules of the human lymphocyte antigen (HLA) define both susceptibility to and protection from T1D. However, T1D is a polygenic disorder with more than 20 loci associated with susceptibility or resistance to the disease, of which the HLA may account for less than 50% of the genetic predisposition. Genetics clearly comprises a major component of the development of T1D, but the interaction between the environment and the immune system abnormalities is believed to weigh heavily in disease development. Indeed, trends in T1D incidence, both geographic and temporal, suggest a strong …

High prevalence of coeliac disease in siblings of children with type 1 diabetes.

Coeliac disease has been shown to occur more frequently among first-degree relatives of diabetic patients than in the general population. Our objective was to assess the prevalence of endomysium antibodies (EMA) in non-diabetic siblings of Czech diabetic children and to evaluate the effects of HLA-DQ polymorphisms in determining the genetic susceptibility to coeliac disease (CD) in these subjects. We investigated 240 siblings of diabetic children from 213 families (125 males and 115 females, aged 12.6+/-4.9 years, mean +/- SD). All subjects were tested for the total IgA level to exclude IgA deficiency, and for endomysium IgA to disclose CD. In five IgA-deficient subjects, anti-gliadin IgG was used instead. Small bowel biopsy was offered to subjects with confirmed positive EMA. The HLA-DQA1, -DQB1 genotypes were determined using PCR-SSP. Positive EMA were found in 9/240 (3.8%) subjects (three males, six females). The biopsy confirmed CD in six children, two had a normal mucosal finding and one refused the biopsy. The HLA-DQ2 polymorphism was more frequent among siblings with EMA (seven of nine) than in siblings without EMA (33%), corrected P = 0.031. The 3.8% frequency of coeliac disease found in siblings of diabetic children is close to the 4.3% found previously in Czech children with type 1 diabetes mellitus and is substantially higher than the rate in the healthy children population.

Redox status and immune function in type I diabetes families.

Because abnormalities in redox balance cluster in type I diabetes families and the intracellular thiol redox status seems to modulate immune function, we aimed to investigate the relationship between oxidative stress and immunological features. We measured oxidative markers, serum proinflammatory cytokines, soluble cytokine receptors and subsets of peripheral blood lymphocytes (by varying combinations of CD4, CD8, CD23 or low-affinity IgE receptor, and CD25 or IL-2 receptor) from 38 type I patients, 76 low-risk (i.e. without underlying islet autoimmunity) non-diabetic first-degree relatives of diabetic patients, and 95 healthy subjects. In type I diabetes families, protein and lipid oxidation was confirmed by the presence of reduced sulphhydryl groups, increased advanced oxidation protein products, and increased plasma and erythrocyte malondialdehyde. Relatives had decreased counts of monocytes, of cells co-expressing CD23 and CD25 and of CD25(+) cells in peripheral blood. Patients with TIDM had similar defects and, in addition, showed decreased counts of peripheral CD4(+)CD8(+) lymphocytes and increased serum levels of soluble receptors for interleukin (IL)-6 and IL-2. Abnormal indicators of oxidative stress were related in part to immune abnormalities. In the whole study group, we found a correlation (multiple R 0.5, P < 0.001) of CD23(+)CD25(+) cells with blood counts of monocytes, CD4(+)CD8(+) cells, CD25(+) cells, basal haemolysis and plasma levels of thiols. In type I diabetics, anti-GAD65 antibody levels were associated (multiple R 0.6, P = 0.01) positively with sIL-6R, negatively with duration of diabetes and CD23(+)CD25(+) counts; plasma creatinine correlated positively (multiple R 0.6, P < 0.001) with both sIL-2R and tumour necrosis factor (TNF)-alpha concentration. Our study reports the first evidence that the oxidative stress observed in type I families is related to immunological hallmarks (decreased peripheral numbers of monocytes as well as cells bearing a CD4(+)CD8(+), CD23(+)CD25(+) and CD25(+) phenotype) from which the involvement of some immunoregulatory mechanisms could be suspected. It remains to be elucidated the course of events culminating in the loss of physiological immune homeostasis and disease pathology.

Review: The genetics of macrovascular disease in diabetes

Patients with diabetes mellitus show an increased risk of developing macrovascular disease. Although common cardiovascular risk factors are abnormally high in patients with type 2 diabetes compared to the general population, they cannot fully explain the high rate of vascular complications. Indeed the occurrence and the severity of such complications are highly heterogeneous even in patients with comparable levels of glycaemic control and similar prevalence of cardiovascular risk factors. Large-vessel atherosclerosis can precede the clinical manifestation of diabetes. This suggests that both atherosclerosis and type 2 diabetes may have common genetic and environmental antecedents. A large body of evidence supports the possible role of genetics in determining the expression of the ischaemic vascular phenotype in diabetic patients, mainly derived from studies in ethnic groups or in first-degree relatives of diabetic patients and from association studies with genetic polymorphisms. Unravelling the polygenic susceptibility factors for macrovascular complications of diabetes is difficult, since diabetes per se has multifactorial inheritance. Direct evidence is largely based on the candidate gene approach in case-control studies. Several systems provide candidate genes that could by themselves or by interacting with other factors, increase the risk of ischaemic vascular disease in diabetic patients mainly related to lipid metabolism, lipoprotein oxidation and haemostatic processes.